The present invention relates to new substituted salicylic acid salts of salmeterol, processes for preparing them and their use as pharmaceutical compositions.
The problem of the present invention is to prepare salts of salmeterol which are characterised by a high degree of local compatibility, particularly when administered by inhalation.
This problem is solved with the substituted salicylic acid salts of formula 1 shown below. Accordingly, the present invention relates to salts of general formula 1
wherein
R1 and R2 which may be identical or different, denote hydrogen, C1-C4-alkyl, C1-C4-alkoxy, halogen, COOH, OH, xe2x80x94COOC1-C4-alkyl, xe2x80x94COxe2x80x94C1-C4-alkyl, xe2x80x94NH2, xe2x80x94NH(C1-C4-alkyl), xe2x80x94N(C1-C4-alkyl)2, xe2x80x94SO2xe2x80x94OH, xe2x80x94CF3 or phenyl;
R3 denotes hydrogen, C1-C4-alkyl, C1-C4-alkoxy, halogen, xe2x80x94CF3 or phenyl, while the phenyl ring may optionally be mono-, di- or trisubstituted by one, two or three groups selected from among C1-C4-alkyl, C1-C4-alkoxy, halogen or xe2x80x94CF3,
xe2x80x83with the proviso that not all the groups R1, R2 and R3 may simultaneously represent hydrogen,
optionally in the form of the enantiomers, mixtures of enantiomers or racemates thereof.
Preferred are salts of formula 1, wherein
R1 and R2 which may be identical or different, denote hydrogen, methyl, ethyl, propyl, butyl, methoxy, ethoxy, fluorine, chlorine, bromine, iodine, COOH, OH, xe2x80x94COOmethyl, xe2x80x94CO-methyl, xe2x80x94NH2, xe2x80x94NH(methyl), xe2x80x94N(methyl)2, xe2x80x94NH(ethyl), xe2x80x94N(ethyl)2, xe2x80x94SO2xe2x80x94OH, xe2x80x94CF3 or phenyl;
R3 denotes hydrogen, methyl, ethyl, propyl, butyl, methoxy, ethoxy, fluorine, chlorine, bromine, iodine, xe2x80x94CF3 or phenyl, while the phenyl ring may optionally be mono-, di- or trisubstituted by one, two or three groups selected from among methyl, ethyl, propyl, butyl, methoxy, ethoxy, fluorine, chlorine, bromine, iodine or xe2x80x94CF3,
xe2x80x83with the proviso that not all the groups R1, R2 and R3 may simultaneously represent hydrogen,
optionally in the form of the enantiomers, mixtures of enantiomers or racemates thereof.
Particularly preferred are salts of formula 1, wherein
R1 and R2 which may be identical or different, denote hydrogen, methyl, ethyl, propyl, methoxy, fluorine, chlorine, bromine, iodine, xe2x80x94COOH, OH, xe2x80x94COOmethyl, xe2x80x94CO-methyl, xe2x80x94NH2, xe2x80x94SO2xe2x80x94OH or xe2x80x94CF3;
R3 denotes hydrogen, methyl, ethyl, methoxy, fluorine, chlorine, xe2x80x94CF3 or phenyl, while the phenyl ring may optionally be mono- or disubstituted by one or two groups selected from among fluorine, chlorine, bromine or xe2x80x94CF3,
xe2x80x83with the proviso that not all the groups R1, R2 and R3 may simultaneously represent hydrogen,
optionally in the form of the enantiomers, mixtures of enantiomers or racemates thereof.
Of particular importance according to the invention are compounds of formula 1 wherein
R1 and R2 which may be identical or different denote hydrogen, methyl, propyl, methoxy, chlorine, iodine, xe2x80x94COOH, OH, xe2x80x94COOmethyl, xe2x80x94CO-methyl, xe2x80x94NH2 or xe2x80x94SO2xe2x80x94OH;
R3 denotes hydrogen or phenyl, while the phenyl ring may optionally be mono- or disubstituted by one or two groups, preferably a group selected from among fluorine, chlorine, bromine or xe2x80x94CF3,
xe2x80x83with the proviso that not all the groups R1, R2 and R3 may simultaneously represent hydrogen,
optionally in the form of the enantiomers, mixtures of enantiomers or racemates thereof.
Especially preferred according to the invention are compounds of general formula 1 wherein
R1 and R2 which may be identical or different, denote hydrogen, methyl, propyl, methoxy, chlorine, iodine, xe2x80x94COOH, OH, xe2x80x94COOmethyl, xe2x80x94CO-methyl, xe2x80x94NH2 or xe2x80x94SO2xe2x80x94OH;
R3 denotes hydrogen,
xe2x80x83with the proviso that not all the groups R1, R2 and R3 may simultaneously represent hydrogen,
optionally in the form of the enantiomers, mixtures of enantiomers or racemates thereof.
Also of especial importance according to the invention are compounds of formula 1 wherein
R1 and R2 denote hydrogen;
R3 denotes phenyl, while the phenyl ring may optionally be mono- or disubstituted by one or two groups, preferably a group selected from among fluorine, chlorine, bromine or xe2x80x94CF3, preferably fluorine,
optionally in the form of the enantiomers, mixtures of enantiomers or racemates thereof.
The alkyl groups used, unless otherwise stated, are branched and unbranched alkyl groups having 1 to 4 carbon atoms. Examples include: methyl, ethyl, propyl or butyl. The groups methyl, ethyl, propyl or butyl may optionally also be referred to by the abbreviations Me, Et, Prop or Bu. Unless otherwise stated, the definitions propyl and butyl also include all possible isomeric forms of the groups in question. Thus, for example, propyl includes n-propyl and iso-propyl, butyl includes iso-butyl, sec. butyl and tert.-butyl, etc.
The alkyloxy groups used, unless otherwise stated, are branched and unbranched alkyl groups with 1 to 4 carbon atoms which are linked via an oxygen atom. The following may be mentioned, for example: methyloxy, ethyloxy, propyloxy or butyloxy. The groups methyloxy, ethyloxy, propyloxy or butyloxy may optionally also be referred to by the abbreviations MeO, EtO, PropO or BuO. Unless otherwise stated, the definitions propyloxy and butyloxy also include all possible isomeric forms of the groups in question. Thus, for example, propyloxy includes n-propyloxy and iso-propyloxy, butyloxy includes iso-butyloxy, sec. butyloxy and tert.-butyloxy, etc. The word alkoxy may also possibly be used within the scope of the present invention instead of the word alkyloxy. The groups methyloxy, ethyloxy, propyloxy or butyloxy may optionally also be referred to as methoxy, ethoxy, propoxy or butoxy.
Within the scope of the present invention halogen denotes fluorine, chlorine, bromine or iodine. Unless otherwise stated, fluorine and bromine are the preferred halogens. The group CO denotes a carbonyl group.
The salts of formula 1 are new acid addition salts of salmeterol, which is known from the prior art. Salmeterol has a chiral centre. The present invention relates to the salts of formula 1 in racemic or enantiomerically pure form. Both the (R)- and the (S)-enantiomer are of particular importance. Moreover the present invention relates to the salts of formula 1 in the form of the non-racemic mixtures of the two enantiomers.
In the compounds of general formula 1 the groups R1, R2 and R3, if they do not represent hydrogen, may each be in the ortho, meta or para position relative to the linking to the carboxyl group. If none of the groups R1, R2 and R3 denotes hydrogen, the group R3 is preferably linked in the meta position and the groups R1 and R2 are linked in the ortho and/or para position. If one of the groups R1, R2 and R3 denotes hydrogen, preferably at least one of the other groups is linked in the meta or para position, most preferably in the para position. Compounds wherein the group R3 does not denote hydrogen are of particular importance according to the invention. In these compounds the group R3 is preferably in the meta position, in relation to the carboxyl group.
The salts 1 according to the invention may be prepared starting from the free base of salmeterol analogously to processes known in the art for forming acid addition salts from secondary amines.
The preparation method comprises reacting the free base salmeterol with carboxylic acids of formula 2
wherein the groups R1, R2 and R3 are as hereinbefore defined, in suitable solvents, preferably organic solvents.
For this purpose the acid 2 is taken up in a suitable solvent, preferably an organic solvent, most preferably a solvent selected from among ethyl acetate, methanol, ethanol, iso-propanol and diethylether or mixtures thereof. If desired the abovementioned solvents may also be used in admixture with tert.-butylmethylether or cyclohexane. The acids 2 taken up in one of the abovementioned solvents are optionally dissolved with heating, preferably to the boiling temperature of the solvent. Salmeterol, optionally dissolved in one of the abovementioned solvents, is added to this solution. The salts 1 are crystallised and isolated from the resulting solution, optionally with cooling.
As has been found, the compounds of general formula 1 are characterised by their range of uses in the therapeutic field. Particular mention should be made of those applications for which the compounds of formula 1 according to the invention may preferably be used on the basis of their pharmaceutical activity as betamimetics.
These include, for example, the treatment of bronchial asthma (normally irritation-induced attacks of bronchial spasm with swelling of the mucosa and increased production of mucus), the treatment of COPD (chronic obstructive bronchitis), the inhibition of premature labour and threatened miscarriage in midwifery (tocolysis), the restoration of the sinus rhythm in the heart in cases of atrio-ventricular block as well as the correcting of bradycardiac heart rhythm disorders (antiarrhythmic agent), the treatment of circulatory shock (vasodilatation and increasing the heart-time volume) as well as the treatment of itching and skin inflammation. The salts of formula 1 are preferably used in the treatment of asthma or COPD.
The salts of general formula 1 may be used on their own or in conjunction with other active substances. These may be, in particular, anticholinergics, antiallergics, leukotriene antagonists, dopamine agonists, PDEIV inhibitors and corticosteroids as well as combinations of active substances.
Examples of anticholinergics which may be mentioned include ipratropium bromide, oxitropium bromide and particularly tiotropium bromide. Drug combinations which contain tiotropium bromide as an additional active substance as well as the compound of formula 1 according to the invention are particularly preferred according to the invention. Combinations which contain, in addition to the compound of formula 1, crystalline tiotropium bromide monohydrate which may be obtained by the experimental procedure described in the experimental section are of particular importance.
This combination is particularly important in the treatment of asthma or COPD, particularly COPD.
Within the scope of the present invention, the corticosteroids which may optionally be used in conjunction with the compound of formula 1 may be compounds selected from among flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide and dexamethasone. Preferably, within the scope of the present invention, the corticosteroids are selected from among flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide and dexamethasone, while budesonide, fluticasone, mometasone and ciclesonide are important and budesonide and fluticasone are particularly important. In some cases, within the scope of the present patent application, the term steroids is used on its own instead of the word corticosteroids. Any reference to steroids within the scope of the present invention includes a reference to salts or derivatives which may be formed from the steroids. Examples of possible salts or derivatives include: sodium salts, sulphobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates. In some cases the corticosteroids may also occur in the form of their hydrates.
Within the scope of the present invention, the term dopamine agonists, which may optionally be used in conjunction with the compound of formula 1, denotes compounds selected from among bromocriptine, cabergolin, alpha-dihydroergocryptine, lisuride, pergolide, pramipexol, roxindol, ropinirol, talipexol, tergurid and viozan. It is preferable within the scope of the present invention to use, as combination partners with the compound of formula 1, dopamine agonists selected from among pramipexol, talipexol and viozan, pramipexol being of particular importance. Any reference to the abovementioned dopamine agonists also includes, within the scope of the present invention, a reference to any pharmacologically acceptable acid addition salts and hydrates thereof which may exist. By the physiologically acceptable acid addition salts thereof which may be formed by the abovementioned dopamine agonists are meant, for example, pharmaceutically acceptable salts selected from among the salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid and maleic acid.
Examples of antiallergic agents which may be used according to the invention as a combination with the compound of formula 1 include epinastin, cetirizin, azelastin, fexofenadin, levocabastin, loratadine, mizolastin, ketotifen, emedastin, dimetinden, clemastine, bamipin, cexchloropheniramine, pheniramine, doxylamine, chlorophenoxamine, dimenhydrinate, diphenhydramine, promethazine, ebastin, desloratidine and meclizine. Preferred antiallergic agents which may be used within the scope of the present invention in combination with the compounds of formula 1 according to the invention are selected from among epinastin, cetirizin, azelastin, fexofenadin, levocabastin, loratadine, ebastin, desloratidine and mizolastin, epinastin and desloratidine being particularly preferred. Any reference to the above-mentioned antiallergic agents also includes, within the scope of the present invention, a reference to any pharmacologically acceptable acid addition salts thereof which may exist.
Examples of PDE-IV inhibitors which may be used according to the invention as a combination with the compound of formula 1 include compounds selected from among enprofylline, roflumilast, ariflo, Bay-198004, CP-325,366, BY343, D-4396 (Sch-351591), V-11294A and AWD-12-281. Preferred PDE-IV inhibitors are selected from among enprofylline, roflumilast, ariflo and AWD-12-281. Any reference to the abovementioned PDE-IV inhibitors also includes, within the scope of the present invention, a reference to any pharmacologically acceptable acid addition salts thereof which may exist. By the physiologically acceptable acid addition salts which may be formed by the abovementioned PDE-IV inhibitors are meant, for example, pharmaceutically acceptable salts selected from among the salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid and maleic acid. According to the invention, the salts selected from among the acetate, hydrochloride, hydrobromide, sulphate, phosphate and methanesulphonate are preferred.
Suitable preparations for administering the salts of formula 1 include for example tablets, capsules, suppositories and powders, etc. The content of the pharmaceutically active compound(s) should be in the range from 0.05 to 90 wt.-%, preferably 0.1 to 50 wt.-% of the composition as a whole. Suitable tablets may be obtained, for example, by mixing the active substance(s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets may also comprise several layers.
Coated tablets may be prepared accordingly by coating cores produced analogously to the tablets with substances normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or prevent incompatibilities the core may also consist of a number of layers. Similarly the tablet coating may consist of a number or layers to achieve delayed release, possibly using the excipients mentioned above for the tablets.
Syrups or elixirs containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. a flavouring such as vanillin or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.
Capsules containing one or more active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatine capsules.
Suitable suppositories may be made for example by mixing with carriers provided for this purpose, such as neutral fats or polyethyleneglycol or the derivatives thereof. Excipients which may be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. groundnut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk), synthetic mineral powders (e.g. highly dispersed silicic acid and silicates), sugars (e.g. cane sugar, lactose and glucose), emulsifiers (e.g. lignin, spent sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulphate).
The preparations are administered by the usual methods, preferably by inhalation in the treatment of asthma or COPD.
For inhalation the compounds may be in the form of inhalable powders, propellant-containing inhalable solutions or suspensions or propellant-free inhalable solutions or suspensions.
The inhalable powders which may be used and are preferred within the scope of the invention may contain the salts 1 either on their own or in admixture with suitable physiologically acceptable excipients. If the salts 1 are present in admixture with physiologically acceptable excipients, the following physiologically acceptable excipients may be used to prepare these inhalable powders according to the invention: monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, saccharose, maltose), oligo- and polysaccharides (e.g. dextrane), polyalcohols (e.g. sorbitol, mannitol, xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures of these excipients with one another. Preferably, mono- or disaccharides are used, while the use of lactose or glucose is preferred, particularly, but not exclusively, in the form of their hydrates. For the purposes of the invention, lactose is the particularly preferred excipient, while lactose monohydrate is most particularly preferred.
The inhalation aerosols containing propellant gas which may be used according to the invention may contain the salts 1 dissolved in the propellant gas or in dispersed form. The propellant gases which may be used to prepare the inhalation aerosols are known from the prior art. Suitable propellant gases are selected from among hydrocarbons such as n-propane, n-butane or isobutane and halohydrocarbons such as preferably fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. The propellant gases mentioned above may be used on their own or in mixtures thereof. Particularly preferred propellant gases are fluorinated alkane derivatives selected from TG134a (1,1,1,2-tetrafluoroethane), TG227 (1,1,1,2,3,3,3-heptafluoropropane) and mixtures thereof.
The propellant-driven inhalation aerosols which may be used according to the invention may also contain other ingredients such as co-solvents, stabilisers, surfactants, antioxidants, lubricants and pH adjusters. All these ingredients are known in the art.
If the salts 1 according to the invention are administered in the form of propellant-free inhalable solutions and suspensions, the solvent used may be an aqueous or alcoholic, preferably an ethanolic solution. The solvent may be water on its own or a mixture of water and ethanol. The relative proportion of ethanol compared with water is not limited but the maximum is up to 70 percent by volume, more particularly up to 60 percent by volume and most preferably up to 30 percent by volume. The remainder of the volume is made up of water. The solutions or suspensions containing 1 are adjusted to a pH of 2 to 7, preferably 2 to 5, using suitable acids. The pH may be adjusted using acids selected from inorganic or organic acids. Examples of particularly suitable inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid and/or phosphoric acid. Examples of particularly suitable organic acids include ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and/or propionic acid etc. Preferred inorganic acids are hydrochloric and sulphuric acids. Of the organic acids, ascorbic acid, fumaric acid and citric acid are preferred. If desired, mixtures of the above acids may be used, particularly in the case of acids which have other properties in addition to their acidifying qualities, e.g. as flavourings, antioxidants or complexing agents, such as citric acid or ascorbic acid, for example. According to the invention, it is particularly preferred to use hydrochloric acid to adjust the pH.
For oral administration the tablets may, of course contain, apart from the above-mentioned carriers, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatine and the like. Moreover, lubricants such as magnesium stearate, sodium lauryl sulphate and talc may be used at the same time for the tabletting process. In the case of aqueous suspensions the active substances may be combined with various flavour enhancers or colourings in addition to the excipients mentioned above.
The dosage of the compounds according to the invention is naturally highly dependent on the method of administration and the complaint which is being treated. When administered by inhalation the compounds of formula 1 are characterised by a high potency even at doses in the xcexcg range. The compounds of formula 1 may also be used effectively above the xcexcg range. The dosage may then be in the gram range, for example.
The example of synthesis described below serves to illustrate the present invention still further. However, it is to be regarded as only an example of a procedure, illustrating one possible method of obtaining the compound according to the invention, without restricting the invention to the object described below by way of example.